Heretofore, active steroid type contraceptive agents included such material as 17 .alpha.-hydroxyprogestrone, norethisterone (norethynyl testosterone, NET) and levonorgestrel. Subsequently the art developed, as long acting injectable steroid type contraceptives, depo-medroxyprogesterone acetate (Depo-Provera) and norethisterone enanthate (NET enanthate), these latter two agents providing some sustained-release advantages over the earilier known contraceptive agents.
It has now been found that certain other novel steroid esters exhibit improved sustained release characteristics when administered to a human, particularly a female, as an injectable contraceptive or fertility suppressing agent.
The novel steroid esters of the present invention are selected from the group consisting of
(a) an ester of D-17 .alpha.-ethynyl-19-nortestosterone having the following formula ##STR1## wherein R is selected from the group consisting of (1) ##STR2## wherein R.sub.1 is lower alkyl, preferably methyl or ethyl and n is 1.6, and PA1 (b) the corresponding oxime of the ester defined in (a); PA1 (c) an ester of levo-norgestrel, i.e., d(+) norgestrel having the formula ##STR3## wherein R.sub.2 is acyl derived from an alicyclic carboxylic acid wherein the alicyclic moiety can have 3-6, preferably 3 and 4, carbon atoms in the ring; PA1 (d) the corresponding oxime of the ester defined in (c); PA1 (e) an ester of levo-norgestrel having the formula (II) above, wherein R.sub.2 is acyl derived from an aliphatic carboxylic acid containing 5 carbon atoms, in extenso pentanoic acid isomers, i.e. ##STR4## (f) the corresponding oxime of the ester defined in (e); (g) an ester of levo-norgestrel having the formula (II) above, wherein R.sub.2 is an acyl derived from an aliphatic carboxylic acid containing 3 and 4 carbon aoms, i.e., propionic acid and butyric acid isomers; PA1 (h) the corresponding oxime of the ester defined in (g); and PA1 (i) an ester of levo-norgestrel having the formula (II) above, wherein R.sub.2 is an acyl chain as defined in (a).
(2) acyl derived from an alicyclic carboxylic acid wherein the alicyclic moiety can have 3-8 carbon atoms in the ring, the ring being substituted by alkyl having 1-8 carbon atoms and preferably by methyl or ethyl;
Representative steroid esters defined in (a) (1) and (i) above are those produced by the esterification of D-17 .alpha.-ethynyl-19-nortesterone and levo-norgestrel with a .beta.-(5-lower alkylene-2 furyl) lower alkanoic acid, preferably a propanoic acid derivative, wherein the 5-lower alkylene substituent, i.e. --(CH.sub.2)n has 1-6 carbon atoms and preferably is methyl or ethyl. Examples of preferred acids include .beta.-(5-methyl-2-furyl) propionic acid and .beta.-(5-ethyl-2-furyl) propionic acid. With these preferred acids, R in Formula I and Formula II can be defined as ##STR5##
Representative steroid esters defined in (a) (2) above are those produced by the esterification of D-17 .alpha.-ethynyl-19-nortesterone and an alicyclic carboxylic acid wherein the alicyclic moiety has 3-8 carbon atoms in the ring. The ring is also substituted by alkyl having 1-8 carbon atoms, this alkyl substituent being either in the cis or trans configuration, the trans configuration being preferred. In these alicyclic carboxylic acids, the ring is preferably cyclohexyl, although certainly it can also be, for instance cyclopentyl or cycloheptyl. Thus, in Formula I, above, R can be defined as ##STR6## wherein Cyc is a cycloalkyl ring having 3-8 carbon atoms and the alkyl substituent, in the cis or trans configuration, has 1-8 carbon atoms. Preferably, then, R can be defined as ##STR7## or more preferably as ##STR8## wherein -- alkyl and - - - alkyl represent, respectively, the cis and trans configuration of the alkyl substituent. When the more preferred acids, i.e. trans-4-methyl-cyclohexane carboxylic acid and trans-4-ethyl-cyclohexane carboxylic acids are employed, R in Formula I can be defined as ##STR9## respectively.
Representative steroid esters defined in (c) above are those produced by the esterification of levo-norgestrel and an alicyclic carboxylic acid wherein the alicyclic moiety has 3-6, and preferably 3 and 4, carbon atoms. Thus in Formula II, above, R.sub.2 can be defined as ##STR10## wherein Cyc is a cycloalkyl ring having 3-6 carbon atoms. Preferably then, R.sub.2 can be defined as ##STR11## when cyclopropane and cyclobutane carboxylic acid are employed in the esterification reaction.
Representative steroid esters defined in (e) above are those produced by the esterification of levo-norgestrel and an aliphatic carboxylic acid wherein the aliphatic moiety has four and five carbon atoms. Thus in formula (II) above, R.sub.2 can be defined as ##STR12##
The novel steroid esters of this invention can be prepared, for instance, by esterifying the D-17 .alpha.-ethynyl-19-nortesterone with the organic carboxylic acid in the presence of benzene sulphonyl chloride, as the coupling agent.
Generally, an equimolar ratio of carboxylic acid:benzene sulphonyl chloride is employed. The organic acid, dissolved in pyridine, is reacted with a molar equivalent of benzene sulphonyl chloride and the resulting mixture is left to stand at ambient temperature for a period of time sufficient to provide the corresponding anhydride.
Thereafter the D-17 .alpha.-ethynyl-19-nortesterone, dissolved in pyridine, is added and the reaction is monitored by thin layer chromatography.
At the completion of the reaction, the reaction mixture is poured onto ice and extracted with chloroform. The chloroform layer is washed several times with dilute HCl, water, aqueous sodium carbonate and finally with water.
The resulting organic layer is dried using anhydrous sodium sulfate, filtered and thereafter the solvent is evaporated. The resulting residue can then be subjected to IR, UV and NMR analysis and either recrystallized or separated by TLC to yield pure compounds.
Alternatively, the novel steroid esters of this invention can also be prepared by esterifying levo-norgestrel with the organic carboxylic acid in the presence of trifluoroacetic acid anhydride in anhydrous benzene solution.
Several other methods are available for the preparation of the steroid esters of the present invention. These other methods often require the protection of the 3-keto function (see J. Chem. Soc. 1963, 3578, Evans et al), the activation of the 17-hydroxy group via a lithium salt (see J. Org. Chem., 1970, 35, 1198, Kaiser et al) or a thallium salt (see Synth. Comm. 1977, 7, 383, Herz et al) and conversion of the carboxylic acid into the more reactive chloride (see J.A.C.S. 1957, 79, 4472, Gould et al, Herz et al supra or Kaiser et al supra), or anhydride (see Canad. J. Chem., 1968, 46, 351, Crabbe et al).
Specifically, using a thallous salt, the following esterification procedure can be employed.
To a solution of 8.95 g (0.03 mol) of D-17.alpha.-ethynyl-19-nortesterone in 100 ml of dry benzene, there are added, with stirring, 2.3 ml (0.033 mol) of thallous ethoxide. Although the benzene distills off slowly, the volume of the reaction mixture is maintained at about 100 ml by the dropwise addition of dry benzene thereto. After 200 ml of benzene have been distilled off, the reaction mixture is cooled in an ice-water bath and the carboxylic acid, in acyl halide form (0.036 mol), is added dropwise thereto. The resulting mixture is refluxed for 5 hours and thereafter cooled and filtered through a bed of kieselguhr. The resulting precipitate is washed with 20 ml of benzene, five times and the solvent then evaporated. The resulting residue is then purified by column chromatography (silica gel) using a 20:80 mixture of chloroform and petroleum ether as the eluant. Alternatively, the residue can be purified by HPLC (silica gel) using a 1:1 mixture of chloroform and n-hexane as the eluant and collecting the main first peak. Still another purification operation can be effected using TLC (silica gel) with a 95:5 mixture of chloroform and ethyl acetate as the eluant. The ester yield, in accordance with this procedure, is about 70 to 90%.
The above thallous ethoxide method can also be employed in the esterification of levo-norgestrel. The only difference is that the ratio of levo-norgestrel:thallous ethoxide:acyl halide is 1:1.2:1.3 moles. The ester yield is about 60-80% using purification methods similar to those described above.
The following non-limiting specific examples illustrate the present invention.